Abstracts

Rationale: We have developed a model of soman-induced status epilepticus (SE) relevant to the pediatric population (Toxicol Appl Pharmacol. 2015, 284(2):204-216) and have shown that the combination of LY293558 and caramiphen (CRM) was the most effective treatment against soman-induced seizures, when compared with each drug alone or with diazepam (J Pharmacol Exp Ther. 2018, 365(2):314-326). However, since only analysis of behavioral seizures was used, characterization of electrographic (EEG) seizures induced by soman in the specific model has not been shown before. In the present study, we show the analysis of EEG during SE and the efficacy of the combined treatment with LY293558 + CRM to terminate soman-induced SE, in 21-day-old (P21) rats. Methods: We exposed electrode-implanted P21 rats to 1.2xLD50 (74.4 µg/kg) soman. The animals received atropine sulfate (0.5 mg/kg) and HI-6 (125 mg/kg) 1 min after exposure, and 60 min later received a combination of LY293558 (10 mg/kg) and CRM (50 mg/kg). We analyzed EEG parameters such as seizure induction and cessation, and power analysis of signals during SE and after injection of LY293558 + CRM, up to 24 hours after treatment. Results: Soman induced self-sustained electrographic spikes of high frequency and amplitude that lasted more than 5 min (SE) in 80% (12/15) of the animals and the latency to SE was 10.4 +- 1.6 min (n=12). The time to terminate SE after animals received LY293558+CRM was 14.0 +- 2.1 min (n=6). Soman-induced SE showed an overall increase in EEG power compared to baseline with an increase of 1.5 times in integrated power (mV2/Hz) from 0.46 +- 0.08 (baseline) to 1.16 +- 0.17 (50 min after exposure); p=0.002. After injection of LY293550+CRM there was a gradual reduction in integrated power, as follows: 30 min after treatment it was 0.45 times above baseline (0.67 +- 0.3; p=0.43); 60 min after treatment it was 0.5 times below baseline (0.22 +- 0.02; p=0.03). From 60 min after treatment there was a gradual increase in integrated power, and at 180 min after treatment it was 0.3 times below baseline (0.31+- 0.04; p=0.07), reaching the maximum value of 0.43 times above baseline (0.66 +- 0.3; p=0.26) at 1120 min after treatment. Conclusions: The EEG analysis confirmed the results obtained using behavioral seizure scores and provides an accurate timeline of the efficacy of combined treatment with LY293558 and CRM against soman-induced seizures. Funding: Supported by USUHS (#H070SG), NIH/NINDS CounterACT Program (#1 U01 NS102135-01A1).The views expressed in this abstract are those of the author(s) and do not reflect the official policy of the Department of Army, Department of Defense, or the U.S. Government. The experimental protocol was approved by the Animal Care and Use Committee at the United States Army Medical Research Institute of Chemical Defense (USAMRICD), and all procedures were conducted in accordance with the principles stated in the Guide for the Care and Use of Laboratory Animals, the Public Health Service Policy on Humane Care and Use of Laboratory Animals and the Animal Welfare Act of 1966 (P.L. 89-544), as amended.